The library generated from solution phase remains a useful methodology in combinatorial chemistry. Above all, the approach is centered around easily synthesized compound class such as amides, sulfonamides, ureas and efficiently prepared heterocycles such as thiazoles (Combinatorial chemistry a practical approach. ed. By Willi Bannworth and Eduard Felder. Wiley-VCH verlag GmbH, Weinheim, 2000). For example, the recent report of a solution-phase derived library in combination with an in-situ cellular screening assay had discovered two amide analogs of fenbufen and ethacrynic acid (EA) with antitumor potencies (Chem. Pharm. Bull. 57(7) 714-718, 2009).

Obviously, the cytotoxicities are mainly attributed to the butyl group. The structural analysis of butyl ethacrynic amide with molecular docking (MD) showed that the butyl group lied in the deep pocket site of glutathiontransferase. MD also showed that a loose space beyond the butyl group was available for further structural modification. By contrast, a reversal orientation was adopted in the case of docking for butyl fenbufen (N-butyl-4-biphenyl-4-oxybutanamide) and cylooxygenase (COX-2). Whereas the antitumor effect of ethacynic acid butyl amide (EABA) was suggested to associate with the inhibition of glutathione S-transferase (Cancer Res., 67: (16), 2007), EA butyl ester (EABE), an analog of EABA, displayed more bioactivity than EA due to its rapid entry into cells (Bioorganic & Medicinal Chemistry Letters, 19, 606-609, 2009).